OBJECTIVES: This analysis compared, from a managed care perspective, the economic impact of using lopinavir/ritonavir- vs. nelfinavir-based highly active antiretroviral treatment (HAART) in antiretroviral (ART)-naïve HIV patients. METHODS: The data from a randomized phase III study of lopinavir/ritonavir + 2 nucleoside reverse transcriptase inhibitors (NRTIs) vs. nelfinavir + 2 NRTIs (Protocol ABT-M98-863) in treating ARV-naïve HIV patients were reanalyzed from an effectiveness (vs. efficacy) perspective to estimate drop-out and treatment failure rates, assuming a failure threshold of 400 copies HIV RNA/mL. Patient care protocols based on clinical guidelines, literature review, and physician input were used to model the cost of managing patients who maintained virologic response or who experienced virologic failure. For patients with PI resistance the replacement regimen was 2 protease inhibitors (PI) + 2 NRTIs and for those without PI resistance the regimen was PI + 2 NRTIs. RESULTS: At 60 weeks, lopinavir/ritonavir was superior to nelfinavir in the proportion of patients responding to therapy or experiencing a loss of virologic response with drug resistance. The model projected that fewer lopinavir/ritonavir patients would require change of therapy or additional monitoring, and that patients initiating ART with lopinavir/ritonavir would incur less costs (total savings of $1553), which can be attributed to lower ART ($25,601 vs. $26,825), drug resistance testing ($97 vs. $179), and other costs ($728 vs. $975). The superiority of lopinavir/ritonavir was robust to sensitivity analysis on changes in viral load thresholds for treatment failure (savings of $1264 for a threshold of 1000 copies/mL and $1022 for a threshold of 5000 copies/mL) and alternative replacement regimens (savings of $782 for PI + 2 NRTIs and $1,217 for PI + 2 NRTIs +1 non-NRTI). CONCLUSIONS: Based on this analysis, lopinavir/ritonavir appears to be clinically and economically preferable to nelfinavir as the PI cornerstone of HAART in ART-naïve HIV-infected patients.